There is no end to it.

In Ann Arbor, Mich., the creators of a new autonomous vehicle have designed their robot to operate on local streets — but more so like a bicycle than a car.

Michigan, Georgia and Oklahoma scrambling for final spots.

• Tesla's vehicles are and always have been crammed with great ideas.
• These range from touchscreen interfaces to innovative battery designs to staggering acceleration.
• I've driven or experienced every vehicle Tesla has ever sold or intends to sell in the future.
• Here are all my favorite features, ranked.
• Visit Business Insider's homepage for more stories.

In about two decades, Tesla has done what everyone in the auto industry thought was impossible: create an all-electric brand that could sell hundreds of thousands of vehicles.

Tesla could have done that in a boring or modest way, developing  the equivalent of an electric VW Beetle.

Instead, Tesla made fantastically compelling cars that are fast, look amazing, and are packed with features.

Here's a rundown of all my favorites, ranked from bottom to top:

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Tesla has been in business for 17 years. In that period of time, it's consistently captivated the world not just because it makes all-electric cars, but because those cars have always been packed with cool features.

"Easter eggs" — frivolous little extras that Tesla throws in whenever it does software updates. Owners enjoy finding them.

The Model X's falcon-wing doors. Dramatic, slightly impractical, and a nightmare to manufacture. But Tesla has the only SUV on the road with such an exotic feature.

Bioweapon Defense Mode uses a powerful filtration system to render the interior air quality of the Model X or Model S "hospital grade," according to Tesla.

The Model X's 5,000-pound towing capacity. Nobody ever talks about it, but the Model X can tow a goodly amount for an electric SUV. It's very competitive with gas-powered SUVs that tout their capabilities.

The large, central portrait touchscreen on the Model S and Model X. This mega-tablet interface was a revelation when Tesla first introduced it on the Model S in 2012, but it's now emulated throughout the auto industry. It's actually canted slightly toward the driver.

Aero Wheels on the Model 3. The proprietary design is standard on the vehicle, enhancing airflow, reducing drag, and improving range.

Ludicrous Mode. The acceleration feature — which followed Insane Mode, first rolled for the all-wheel-drive Model S — enables Teslas to cover the 0-60 mph sprint at supercar-like velocities.

Frunks! All Teslas currently on sale have front trunks, expanding their cargo capacities. Having no gas engine helps to free up space.

Trunks! Teslas are commendable cargo haulers because they're effectively boxes on top of battery packs, creating ample space for luggage, groceries, of gear.

Quiet. In operation, Teslas are notably quiet and smooth, thanks to the optimization of airflow, solid build quality, and mostly silent electric motors.

The Tesla smartphone app. I've actually tested a number of these from assorted manufacturers, but Tesla's is the only one that's truly useful. For the Model 3, it replaces the traditional key fob.

The glass roof of the Model 3. It creates a stunning silhouette and floods the cabin with natural light.

The space-age operators' platform in the cab of the Tesla Semi. This space — clearly anticipating a time when semi-trucks drive themselves — is the most futuristic thing Tesla has ever designed.

Roadsters in space. CEO Elon Musk's personal Tesla Roadster was launched atop the SpaceX Falcon Heavy rocket in 2017, as a test payload. Piloted by "Starman," it set a new standard for automotive marketing.

Tesla's in-house audio system. Most luxury brands partner with a big-name audio company for premium sound systems, but Tesla developed its own — and it sounds absolutely fantastic.

Charge monitoring and mapping. Charging is among the most important things Tesla has to think about, so the company has made it a priority to track it in the vehicle and via the app, as well as to plot road-trip courses that use GPS navigation to permit island-hopping from charging location to charging location.

Navigate on Autopilot combines Tesla's GPS mapping system with Autopilot's ability to execute lane changes and freeway on- and off-ramping maneuvers.

The new Roadster's staggering performance specs. The all-new machine has a claimed 0-60 mph time of 1.9 seconds, making it the fastest production vehicle in the world.

The Model 3's consolidated vehicle-management system and central landscape touchscreen. Almost every aspect of the Model 3 is controlled here, and the traditional instrument cluster has been moved to the left side of the screen, and streamlined.

The radical design of the Cybertruck. In late 2019, Tesla had fallen into a design rut. The otherworldly, stainless-steel Cybertruck changed all that. Controversial to be sure, but also thrilling.

Read about the Cybertrucks' rad design.

Manufacturing simplicity. Electric cars are less complicated to build than gas-powered ones. Tesla has designed its factory in China to optimize this aspect of production, which could support and enviable profit margin for Tesla in the 20-30% range.

The white interior. It's an extra, but a very popular one. I was initially skeptical, but I'm now a fan. After all, it survived a 700-plus-mile family road trip!

Read about the road trip.

Over-the-air software updates. Just like smartphones, Teslas can be routinely upgraded while sitting in owners' driveways. This means that an older Tesla can acquire new features quite literally overnight.

The Supercharger network. Access to DC fast-charging used to be a lifetime perk for Tesla owners, but Tesla has begun to bill for the service. Still, it enables longer road trips and is completely integrated with each Tesla vehicle's systems.

Tesla's design philosophy. Head designer Franz von Holzhausen and Elon Musk argue that it doesn't cost anymore to make Teslas beautiful. But von Holzhausen has also exercised tasteful restraint, ensuring that Tesla's vehicles have a long market life.

Read about Franz's design influence.

Performance! Tesla vehicles have always combined electric virtuosity with industry-leading performance. Owners can usually expect to be driving one of the fastest cars on the road.

Battery design. Tesla has taken a complicated, multi-cell concept — thousands are wired together in packs — and perfected it, yielding impressive range and performance. The company also manufactures its own packs, in partnership with Panasonic.

The Model 3's minimalist driving experience. With the clean dashboard, you can focus on the road ahead. It's a blissful thing and my top Tesla feature.

The bottom line is that while plenty of other automakers put cool features in their cars, Teslas are crammed with ideas, ideas, and more ideas.

• Oracle's bid to become a bigger player in the cloud has become more aggressive in the COVID-19 crisis, highlighted by a new partnership with Zoom.
• The tech giant is up against stronger rivals led by Amazon, Microsoft and Google, but the need for more cloud capacity sparked by the sudden pivot to remote work has created opportunities for the Silicon Valley behemoth.
• Here are the 10 Oracle executives who are playing key roles in CEO Safra Catz and founder Larry Ellison bold cloud offensive.
• Click here for more BI Prime stories.

Oracle has been through some jarring changes in the last seven months. 

The tech giant lost a well-regarded and experienced co-CEO when Mark Hurd died in October after taking leave for health reasons, leaving Safra Catz as the solo CEO. Now, like other major tech companies, Oracle is grappling with the impact of the coronavirus crisis.

But Oracle has been through tough times in its 43-year history. In fact, the Silicon Valley giant has been known to seize opportunities during rough spots. It's already seen some success during this crisis, too: Oracle just scored a big win when videoconferencing company Zoom — suddenly facing a surge in demand — chose to expand on Oracle Cloud, instead of other platforms like top cloud provider Amazon. Oracle is generally considered a smaller player in the cloud wars, behind giants Amazon, Microsoft, Google, and Alibaba.

Yes, Oracle still has a long way to go to match its rivals' reach, but its strategy of expanding its capacity by building more data centers seems to be paying off, IDC President Crawford Del Prete told Business Insider.

That increased capacity and Oracle's "world class" applications are key in the cloud words, Del Prete said: "Oracle is one of the few companies able to deliver both at scale in order to compete."

While Catz and founder, executive chairman, and chief technology officer Larry Ellison the lead company, they're also relying on key top executives, including cloud veterans from rival Amazon, to advance Oracle's cloud strategy. 

Nearly all are white men, something Oracle has criticized for in the past: Over 30 members of Congress slammed the company late last year about the lack of diversity in its leadership team and on its board.

Meet the 10 top executives playing important roles in Oracle's cloud offensive:

SEE ALSO: Oracle is known for making bold M&A moves in a recession and it's sitting on a fresh $20 billion. Here are the 7 companies experts think it could acquire as the coronavirus crisis drives down valuations

SEE ALSO: Experts lay out five moves that Oracle founder Larry Ellison, one of tech's best tacticians, might take in a coronavirus-driven downturn

Don Johnson left Amazon to focus on Oracle's cloud infrastructure.

Title: Executive vice president, cloud infrastructure

Reports to: Larry Ellison

Johnson  played a key role in Amazon's dramatic expansion in the cloud before joining Oracle in 2014.

He was instrumental in setting up Oracle's cloud engineering development center in Seattle and in the tech giant's expanding data center footprint.  Johnson has also led another major Oracle initiative: forming a cloud partnership with Microsoft.

Oracle's chief corporate architect Edward Screven has been with the company since 1986.

Title: Chief corporate architect

Reports to: Larry Ellison

Screven is an Oracle veteran who helped lead the company through all of the major industry changes of the past 30 years.

He admits that cloud market-leader Amazon had a head start, but says that there are benefits to following it. 

"We definitely started after Amazon: The bad news is they have market share, the good news is we get to learn a lot," he told Business Insider in an interview in May 2019. "Mindshare, that may be their biggest asset. But there is no technology they have that is concerning to me at all."

As one of Oracle's top technologists, he's focused on making Oracle's cloud infrastructure more secure, with more sophisticated and efficient ways to manage data. 

"We have hundreds of thousands of customers that store their most important data in Oracle databases," Screven said. "We could do a far better job for them than any other cloud provider. We are doing a far better job for them."

Clay Magouyrk leads cloud infrastructure engineering and played a key role in forging Oracle's new alliance with Zoom.

Title: Executive vice president, cloud infrastructure engineering

Reports to: Don Johnson

Magouyrk is another veteran of Amazon Web Services who joined the Oracle team in Seattle in 2014. 

He was Oracle's point-man in forging its new partnership with Zoom, which was seen as a major victory for Oracle.

"They needed capacity," Magouyrk told Business Insider last month "They reached out to us and we were like, 'Awesome, we can work with you.' Within a day, we had their application up and running."

Magouyrk was a founding team member of Oracle's cloud engineering development center in Seattle, which is spearheading the company's cloud infrastructure efforts.

Ariel Kelman left Amazon Web Services to become Oracle's chief marketing officer.

Title: Chief Marketing Officer

Reports to: Safra Catz

One of the biggest hurdles for Oracle is the public perception that it's a minor player in the cloud. In other words, it's a marketing problem.

This is where Kelman comes in. Before Oracle brought him on board in January 2020, Kelman led rival Amazon's cloud marketing efforts, and served as a marketing executive at Salesforce for six years before that.

"Ariel is a super smart hire for Oracle," analyst Ray Wang of Constellation Research told Business Insider. "He brings the cred in the market and understands how to counter all of Amazon's tactics and long-term strategy. He has the ear of Larry and Safra and is making progress with some great hires on his team."

Juergen Lindner left SAP to lead Oracle's software-as-a-service marketing strategy.

Title: Senior vice president, software-as-a-service marketing

Reports to: Ariel Kelman, chief marketing officer

Lindner spent most of his career helping SAP outsell Oracle in the traditional business software market: both dominated teh market for software installed in private data centers. 

He switched sides and roles four years ago to support Oracle's bid to become a stronger player in cloud software, also referred to as software-as-a-service, where businesses access applications through cloud platforms and pay via a subscription, usually based on the number of users granted access. 

Lindner has said it became clear to him that Oracle had a better strategy for the cloud-software era.

"Oracle has architected a very sustainable cloud infrastructure and applications strategy," he told Business Insider last year.

Steve Daheb left Citrix to lead Oracle's cloud marketing strategy.

Title: Senior vice president, cloud go-to-market

Reports to: Ashley Hart, senior vice president, global marketing cloud platform and database

Daheb joined Oracle in 2015 after serving as the chief marketing officer of Citrix, a cloud pioneer that first let businesses set up computing networks on web-based platforms instead of on-premise data centers, leading to dramatic IT cost savings.

Daheb witnessed the unexpected rise of Amazon in cloud computing, which began in the early : 2000s when the online retail giant realized it could make some extra money by giving businesses access to its massive but underutilized computing infrastructure, hosted from its data centers.

"Amazon had spare computing resources to rent out," he told Business Insider last year. "It's like, 'Hey, man, I got an extra room in the house during the summer when it's not spike retail time. There's nobody in there, so why don't I put this thing on Airbnb and see if anybody wants it?'"

Amazon Web Services has led the industry ever since. 

Like others on the Oracle team, Daheb thinks the software giant's technology and track record of working with major players across industries will eventually propel it to the front of the cloud pack.

"There's a level of understanding we have and a level of empathy we have for enterprise users: We serve the major banks, we serve transportation, we serve healthcare," he said. "We brought this enterprise mentality to it."

Juan Loaiza, who has been with Oracle since 1988, is in charge of mission-critical database technologies.

Title: Executive vice president, mission-critical database technologies

Reports to: Larry Ellison

Loaiza is another Oracle veteran who has been with the company for more than 30 years and is currently focused on its bid to expand the reach of its flagship database product.

The tech giant's cloud-based automated data-management platform Autonomous Database uses machine learning to quickly repair and update itself.Loaiza has compared the status of this fairly new initiative to the development of the self-driving car:

"It took a long time to get to a point where we are now and say, 'The next step is a self-driving car,'" he told Business Insider last year. "It's got to be safe. It has to have seatbelts and airbags and a navigation system. All that stuff was necessary before you take it to the next stage." 

The database is ready for that next stage. 

Jason Williamson left Amazon to lead Oracle's outreach to startups.

Title: Vice president, Oracle for Startups

Reports to: Mamei Sun, Ellison's chief of staff

Startups have played an important role in the growth of cloud computing and Oracle has launched a big push to establish closer ties with these smaller companies, given that they could eventually become the biggest power players. 

Williamson has been the company's point-man in this effort, as he develops ways to make Oracle's products and services more accessible to startups.

Williamson is another veteran of Amazon Web Services where he led the cloud giant's private-equity team before joining Oracle in 2017.

Evan Goldberg cofounded NetSuite, which is now part of Oracle.

Title: Executive vice president, NetSuite

Reports to: Safra Catz

Goldberg is part of the elite club of Oracle alums who went on to launch successful enterprise-software companies. (Salesforce CEO Marc Benioff is perhaps the best-known.)

Goldberg left a long career at Oracle in the late 1990s to launch NetSuite, a cloud-based provider of financial- and accounting-management services. He was the chief technology officer alongside CEO Zach Nelson, another Oracle alum, and Ellison was actually one of their early backers.

Oracle acquired the company in 2016 and it now has more than 18,000 customers. 

Steve Miranda has been with Oracle since 1992 and leads cloud-applications development.

Title: Executive vice president, applications product development

Reports to: Ellison

Miranda is an Oracle veteran in charge of different aspects of the company's cloud-software business, including product development and strategy.

This covers applications used for major business operations, like supply-chain management, human resources, and enterprise performance management.

• I tested a roughly $33,000 Polaris Slingshot R, a three-wheeled "autocycle."
• The three-wheeler category includes vehicles from Can-Am and Harley-Davidson, offering a motorcycle experience in a less demanding package.
• My Slingshot R had a new, Polaris-developed, 203-horsepower engine and an automatic transmission.
• In all but three US states, no motorcycle license is required to operate the Slingshot (New York, Massachusetts, and Alaska continue to require the motorcycle certification).
• The Slingshot is insanely fun, with a modest learning curve — it's a great alternative to a two-wheeler, although the price is definitely steep for the Slingshot R.
• Visit Business Insider's homepage for more stories.

Motorcycles are cool, but they aren't for everybody. Fortunately, there are some alternatives out there that offer an equally compelling, open-air experience.

One of the most popular is the the Polaris Slingshot, manufactured by the Minnesota-based powersports company. Until recently, Slingshots were available only with manual transmissions and GM-sourced engines, but for 2020, Polaris has updated the autocycle with an in-house motor and an automatic.

The automatic transmission in particular really broadens the Slingshot's potential. So I was excited to sample the machine, which I first saw about five years ago.

Polaris was kind enough to loan me a tester for a few weeks. Here's how it went:

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The Polaris Slingshot is a three-wheeled autocycle/motorcycle that Polaris industries has produced since 2014. My 2020 Slingshot R tester cost about $33,000 and was outfitted in a menacing red-and-black paint job.

The cheapest Slingshot is about $20,000.

This wasn't my first crack at a Slingshot. Polaris brought the vehicle to Insider's New York offices when the vehicle first launched.

And I generally have a gander at the Slingshot when I visit the annual New York motorcycle show.

The Slingshot is classified as either a motorcycle or an autocycle, depending on which state it's being operated in.

Yep, it looks like the Batmobile. Or Batcycle. Hard to avoid feeling like a superhero when you're behind the wheel. In all but three US states, no motorcycle license is required to drive the Slingshot. In New Jersey, you are required to wear a helmet.

Up front, you have 18-inch forged aluminum wheels, with an 20-incher at the back. The brakes have two-piece composite rotors.

Permanent open-air motoring isn't for everybody. Polaris does sell and older model, the Grand Touring, which has a cockpit canopy. The Polaris R has a waterproof interior and drain holes in the floorboards, should you get caught in bad weather.

My tester was the top-level "R" trim, complete with dual roll bars for drier and passenger.

Let's talk fender fairings! The Slingshot's are dramatic and large — I was reminded of Chevy Corvettes while driving this thing. Like a motorcycle, there's no rear-view mirror, so you have to adjust slightly to using the sideviews.

There's a new engine under the hood. Previously, Polaris used a 2.4-liter, four-cylinder GM-sourced Ecotech motor, making up to 175 horsepower. But my R had a ProStar four, also at 2.4-liters, cranking out 203 horsepower with a five-speed automatic transmission (a manual remains available). It's an in-house engine that was impressive in action.

The top speed is limited at 125 mph, and the 0-60mph run, according to Polaris and confirmed by yours truly, is about five seconds.

The four-banger redlines at 8,500 rpm and even with the automatic transmission does a pretty fair imitation of proper motorcycle acceleration. The auto is a tad crunchy, but in this context, that's a plus. It keeps you aware of what the engine is doing.

The rear wheel — fat and wide — is yoked to the motor and transmission with a belt drive. The suspension is surprisingly compliant, but you do have to be mindful of bumps, potholes, and manhole covers if you want to preserve you lower spine.

Polaris says the interior has been upgraded for 2020. No one would call it premium, but for a vehicle like this, it's rather comfortable.

The steering wheel is leather-wrapped, multifunctioned, and flat-bottomed to make getting into and out of the driver's seat easier.

The instrument cluster is a basic analog affair with a central digital display. The red button to on the right steering-wheel spoke allows you to switch between Comfort and Slingshot modes (the latter being the high-performance option).

The bucket seats are waterproof and extremely well-bolstered, with three-point seat belts.

The Slingshot's tubular frame is apparent in the doorless frame.

Not really much cargo capacity here, although I did use the Slingshot for a grocery-store run and quick jaunt to Target to buy a basketball.

There is a place to stow a smartphone, located just above the push-button gear selector.

The Slingshot also has push-button start-stop.

The glove compartment is the only other storage available ...

... And it's actually pretty roomy. One could stash a rain jacket in there, for example.

The RideCommand infotainment system is basic — but good! On a vehicle such as this, I wasn't expecting much, but the audio setup sounded decent, the screen was responsive, and Bluetooth and USB connectivity was on-par with what you'd find in any modern automobile.

There's even GPS navigation, which can display a map and provide turn-by-turn guidance.

The ride-mode selector is doubled in the infotainment system.

So what's the verdict?

I love three-wheelers. They aren't as cool as two-wheeled motorbikes, but they provide easy access to open-air motoring, and the driving/riding experience is much more engaging than what you find in convertible automobiles.

For anybody who dislikes the impracticality of motorcycles but wants to partake of the open-road lifestyle, machines like the Slingshot (the Can-Am Spyder and the Harley-Davidson Freewheeler, to name two) are ideal.

Not for nothing, they also offer aging riders a chance to yank their helmets and biker jackets out of storage to pursue moderately safer riding. With the Slingshot, gearing-up isn't necessary.

The trade-off, of course, is price. The Slingshot R that I tested costs more than an entry-level car or SUV. So, an expensive plaything. But there's nothing wrong with that. Everybody needs a hobby.

No doubt about it, the Slingshot captures attention. I lost count of how many little kids a stopped in their tracks as I tooled around the Jersey suburbs. The last vehicle that provoked such astonishment was the Lamborghini Huracán Performante. If you become a Slingshotter, prepare to be pointed at and asked for photo-ops.

Driving-wise, the Slingshot scratches an itch: on the road, the experience is unexpurgated — you don't have to be constantly vigilant, as you would on a bike, but you do need to remain aware. Highway trips are demanding. And noisy. And exhilarating. The Slingshot R is also fast and torque-y and the power goes to the single back wheel, so the while the two-wheeled front is stable, the back end can get pretty wiggly, especially in Slingshot mode, if you stomp the throttle.

I had iffy springtime Northeast weather to contend with, so I took the Slingshot out only on warm and sunny days; the rest of the time, I parked it in my garage. But the vehicle can handle being rained on, and one could also buy a cover to protect it from the elements. To be honest, however, I think it's a better choice in warm, dry climates. 

The performance is aggressively go-kart-y. This thing will make you a better drive, thanks to its point-and-shoot steering, crisp suspension, and easy access to power. It's insanely fun on curves and into corners. But it's also worthy of short road trips. In fact, the relative comfort was a shocker: I took the Slingshot out for a few hours one day and suffered no ill-effects to my lower back.

Drawback? The design is thoroughly sporty, so if you don't go in for that, the Slingshot might not be your bag. It isn't a throwback, nor is it at all steam-punky. 

It also isn't a motorcycle, in that there aren't any handlebars, you don't throw a leg, and the single wheel takes up the rear. 

But the Slingshot is a absolute blast, and if you're a weekend warrior who wants to carve up a canyon or a country road without having the grapple with a motorcycle's demands — and you don't mind dropping some dollars — the Slingshot is perfect.

When it comes to getting schooled on plastic water bottles, look no further than Aquaman.

With the lockdown across nations, you are probably spending more time reading. Whether it’s for pleasure or for work, we’re here to help you fill your time with some reading material. These web design articles are not only about best practices, deals, and trends in the niche but also include feel-good stories that we all […]

The post Roundup: Web Design Articles May 8, 2020 appeared first on SpyreStudios.

oscon: RT @andreabledsoe: So proud our #womenintech resource center is live, w/ great articles +enter to win a #OSCON scholarship...

Got potatoes? Going to cook them? Here’s what you need to know for prepping them.

Continue reading "How to Clean and Prep Potatoes for Cooking" »

Wondering about the best way to clean a Le Creuset Dutch oven, and enameled cookware in general? Good news - it's pretty easy!

Continue reading "How Do You Clean Enamel Cookware?" »

Cycling in Tuscany, Italy

In just under five months, both President Donald Trump and former Vice President Joe Biden will, one assumes, step onto a debate stage at the University of Notre Dame in South Bend, Indiana. It’s one heck of an assumption, and for more reasons than one. We don’t know if there are going to be debates…

The post With Debate Months Away, It’s Clear Biden Isn’t Ready for a 1-on-1 with Trump appeared first on The Western Journal.

Ian McKee, founder and CEO of Singapore-based Vuulr, explains the value of blockchain technology—and the threat it poses to the structure of traditional digital advertising.

Christmas is not an official holiday in Japan, nor a widely observed religious holiday, but it is celebrated nonetheless in its own unique way. Here's some data that highlights Christmas in Japan.

Luis Spencer Freitas, digital marketing director at Pernod Ricard USA, explains what will drive greater innovation in display advertising next year.

Radoslaw Dobrolecki, US business development director at RTB House, discusses how artificial intelligence can help predict customer behavior at scale.

Joshua Summers, CEO of linear television supply-side platform clypd, discusses the major advanced targeting trends expected to infiltrate traditional TV ad buying within the next year.

Michael Tiffany, co-founder and president of ad verification and fraud prevention firm White Ops, discusses the next evolution of fraudulent practices for 2018.

Patrick Jones, global vice president and general manager of partnerships for Oracle Data Cloud, discusses how he expects agencies and brands to evolve their use of audience data sets this year.

Omer Golan, founder and CEO of Outernets, discusses how artificial intelligence can improve the digital out-of-home industry.

Dan Greenberg, co-founder and CEO of native advertising solutions provider Sharethrough, discusses how buyers’ increased desire for contextual targeting and native advertising will benefit premium publishers in 2018.

William Bao Bean, managing director of Chinaccelerator, explains how investments in artificial intelligence and machine learning are helping marketers improve user targeting and return on investment.

From better campsite cooking to car maintenance to smartphone-free communication, here are 12 gadgets to up your car camping game.

The post Up Your Car Camping Game with These 12 Clever Gadgets appeared first on Vagabondish.

With the eviction date looming for campers to leave Oppenheimer Park, B.C.'s social development minister says everyone is still expected to be out of the park by Saturday.

The following article, Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom, was first published on 100PercentFedUp.com.

The normalizing of pedophilia is not a far-right conspiracy theory...

Continue reading: Fed Judge Releases 21-Yr-Old Man To “Clean and Sober House” After Appearing In Court For Sexually Assaulting 12-Yr-Old Girl For One Month While Hiding In Her Bedroom ...

Mutations in retinaldehyde-binding protein 1 (RLBP1), encoding the visual cycle protein cellular retinaldehyde-binding protein (CRALBP), cause an autosomal recessive form of retinal degeneration. By binding to 11-cis-retinoid, CRALBP augments the isomerase activity of retinoid isomerohydrolase RPE65 (RPE65) and facilitates 11-cis-retinol oxidation to 11-cis-retinal. CRALBP also maintains the 11-cis configuration and protects against unwanted retinaldehyde activity. Studying a sibling pair that is compound heterozygous for mutations in RLBP1/CRALBP, here we expand the phenotype of affected individuals, elucidate a previously unreported phenotype in RLBP1/CRALBP carriers, and demonstrate consistencies between the affected individuals and Rlbp1/Cralbp−/− mice. In the RLBP1/CRALBP-affected individuals, nonrecordable rod-specific electroretinogram traces were recovered after prolonged dark adaptation. In ultrawide-field fundus images, we observed radially arranged puncta typical of RLBP1/CRALBP-associated disease. Spectral domain-optical coherence tomography (SD-OCT) revealed hyperreflective aberrations within photoreceptor-associated bands. In short-wavelength fundus autofluorescence (SW-AF) images, speckled hyperautofluorescence and mottling indicated macular involvement. In both the affected individuals and their asymptomatic carrier parents, reduced SW-AF intensities, measured as quantitative fundus autofluorescence (qAF), indicated chronic impairment in 11-cis-retinal availability and provided information on mutation severity. Hypertransmission of the SD-OCT signal into the choroid together with decreased near-infrared autofluorescence (NIR-AF) provided evidence for retinal pigment epithelial cell (RPE) involvement. In Rlbp1/Cralbp−/− mice, reduced 11-cis-retinal levels, qAF and NIR-AF intensities, and photoreceptor loss were consistent with the clinical presentation of the affected siblings. These findings indicate that RLBP1 mutations are associated with progressive disease involving RPE atrophy and photoreceptor cell degeneration. In asymptomatic carriers, qAF disclosed previously undetected visual cycle deficiency.

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.

Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Müller glia. In the RPE, isomerization of all-trans-retinyl esters to 11-cis-retinol is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Müller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early, and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, while the emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaptation displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 min of light, early photopic vision was recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the nonphotopic or photopic visual cycles for mediating vision in bright light.

28 April 2020

This paper aims to assist the region’s local authorities, and their key foreign backers, in understanding how transitional justice can provide alternative avenues for holding local ISIS members to account while contributing to the healing of communities.

Research Event

Haid Haid, Senior Consulting Fellow, Middle East and North Africa Programme, Chatham House
Sara Kayyali, Syria Researcher, Middle East and North Africa Division, Human Rights Watch
Moderator: Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

The Moving Energy Initiative starts four new clean energy projects for refugees.

12 March 2015 , Volume 91, Number 2

pncRNA-D is an irradiation-induced 602-nt long noncoding RNA transcribed from the promoter region of the cyclin D1 (CCND1) gene. CCND1 expression is predicted to be inhibited through an interplay between pncRNA-D and RNA-binding protein TLS/FUS. Because the pncRNA-D–TLS interaction is essential for pncRNA-D–stimulated CCND1 inhibition, here we studied the possible role of RNA modification in this interaction in HeLa cells. We found that osmotic stress induces pncRNA-D by recruiting RNA polymerase II to its promoter. pncRNA-D was highly m6A-methylated in control cells, but osmotic stress reduced the methylation and also arginine methylation of TLS in the nucleus. Knockdown of the m6A modification enzyme methyltransferase-like 3 (METTL3) prolonged the half-life of pncRNA-D, and among the known m6A recognition proteins, YTH domain-containing 1 (YTHDC1) was responsible for binding m6A of pncRNA-D. Knockdown of METTL3 or YTHDC1 also enhanced the interaction of pncRNA-D with TLS, and results from RNA pulldown assays implicated YTHDC1 in the inhibitory effect on the TLS–pncRNA-D interaction. CRISPR/Cas9-mediated deletion of candidate m6A site decreased the m6A level in pncRNA-D and altered its interaction with the RNA-binding proteins. Of note, a reduction in the m6A modification arrested the cell cycle at the G0/G1 phase, and pncRNA-D knockdown partially reversed this arrest. Moreover, pncRNA-D induction in HeLa cells significantly suppressed cell growth. Collectively, these findings suggest that m6A modification of the long noncoding RNA pncRNA-D plays a role in the regulation of CCND1 gene expression and cell cycle progression.

Ilka Wittig
Jul 1, 2007; 6:1215-1225
Research

Jesper V. Olsen
Jun 1, 2004; 3:608-614
Technology

Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme involved in ATP generation and critical for cancer metabolism. PKM2 is expressed in many human cancers and is regulated by complex mechanisms that promote tumor growth and proliferation. Therefore, it is considered an attractive therapeutic target for modulating tumor metabolism. Various stimuli allosterically regulate PKM2 by cycling it between highly active and less active states. Several small molecules activate PKM2 by binding to its intersubunit interface. Serine and cysteine serve as an activator and inhibitor of PKM2, respectively, by binding to its amino acid (AA)-binding pocket, which therefore represents a potential druggable site. Despite binding similarly to PKM2, how cysteine and serine differentially regulate this enzyme remains elusive. Using kinetic analyses, fluorescence binding, X-ray crystallography, and gel filtration experiments with asparagine, aspartate, and valine as PKM2 ligands, we examined whether the differences in the side-chain polarity of these AAs trigger distinct allosteric responses in PKM2. We found that Asn (polar) and Asp (charged) activate PKM2 and that Val (hydrophobic) inhibits it. The results also indicate that both Asn and Asp can restore the activity of Val-inhibited PKM2. AA-bound crystal structures of PKM2 displayed distinctive interactions within the binding pocket, causing unique allosteric effects in the enzyme. These structure-function analyses of AA-mediated PKM2 regulation shed light on the chemical requirements in the development of mechanism-based small-molecule modulators targeting the AA-binding pocket of PKM2 and provide broader insights into the regulatory mechanisms of complex allosteric enzymes.

Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.

The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.

The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency.

20 April 2020

Nuclear deterrence theory, with its roots in the Cold War era, may not account for all eventualities in the 21st century. Researchers at Chatham House have worked with eight experts to produce this collection of essays examining four contested themes in contemporary policymaking on deterrence.

1 May 2020

Research Event

Haid Haid, Senior Consulting Fellow, Middle East and North Africa Programme, Chatham House
Sara Kayyali, Syria Researcher, Middle East and North Africa Division, Human Rights Watch
Moderator: Lina Khatib, Director, Middle East and North Africa Programme, Chatham House

Mohamad Navab
Jun 1, 2004; 45:993-1007
Thematic Reviews

Weerapan Khovidhunkit
Jul 1, 2004; 45:1169-1196
Thematic Reviews

RK Tangirala
Nov 1, 1995; 36:2320-2328
Articles

JE Hixson
Mar 1, 1990; 31:545-548
Articles